MITF

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Waardenburg Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

This type of Waardenburg syndrome is distinguished from type 1 and 3 (193500) by the fact that it is caused by mutations in a different gene and in the absence of dystopia canthorum.  It has been claimed that hearing loss is more common and severe in type 2 (77%) as is heterochromia of the iris (47%) while skin and hair hypopigmentation are less common.

Families with WS2A may have the full spectrum of eye findings seen in X-linked ocular albinism I (300500) including decreased acuity, photophobia, nystagmus, translucent irides, hypermetropia, and albinotic fundi with foveal hypoplasia.  Indeed, such families have been considered to have 'albinism, ocular, with sensorineural deafness' (103470).  Such families might be considered to have an autosomal dominant form of ocular albinism.

Systemic Features: 

Congenital sensorineural hearing loss is an important and common feature.  Also characteristic are the white forelock, poliosis, and hypopigmented skin patches.

Genetics

Waardenburg syndrome is an excellent example of genetic heterogeneity as types 1 and 3 (193500, 148820), 2 (193510), and 4 (277580) are all caused by mutations in different genes. 

Type 2 described here is a genetically heterogeneous autosomal dominant disorder.  WS2A is caused by a mutation in MITF (microphthalmia-associated transcription factor) (3p14.1-p12.3).  This is the same disorder described as 'Albinism, ocular, with sensorineural deafness' in OMIM (103470)  (WS2-OA).

A locus at 1p21-p13.3 is associated with WS2B (600193) and WS2C (606662) maps to 8p23.  In addition, homozygous SNAI2 mutations at 8q11 have been found in several patients with WS2D (608890) suggesting autosomal recessive inheritance but the normal parents were not studied.  Recent evidence suggests that SOX10 mutations can also play a role via MITF promoter modulation (WS2E) (611584).

Type 4 is also the result of mutations in at last three genes.

A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3.  Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations.  In addition the face showed marked patchy pigmentation.  One parent contributed the MITF mutation and the other added the mutation in PAX3.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No ocular treatment is necessary but assistive hearing devices can be helpful.

References
Article Title: 
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